The primary hypothesis of this study is that ibrutinib compared with temsirolimus significantly prolongs PFS in subjects with relapsed or refractory MCL who have received at least 1 prior rituximab-containing chemotherapy regimen.
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the study is to evaluate whether treatment with
ibrutinib compared with temsirolimus will result in prolongation of
progression-free survival (PFS) in subjects with relapsed or refractory mantle
cell lymphoma (MCL) who have received at least 1 prior rituximab-containing
chemotherapy regimen.
EFFICACY EVALUATIONS/ENDPOINTS
Disease evaluations (computed tomography [CT]/magnetic resonance imaging [MRI],
clinical evaluation) will be performed every 9 weeks for up to 15 months from
the start of study drug, and every 24 weeks thereafter, until disease
progression, death, or the clinical cutoff, whichever comes first. Subjects who
discontinue treatment prior to disease progression must continue to have
regularly scheduled disease evaluations until disease progression, or death, or
the clinical cutoff, whichever occurs first. For all subjects, the following
data will be collected after the clinical cutoff: survival data, EQ-5D-5L, and
subsequent anti-MCL therapy.
During the Crossover Treatment Phase, radiological assessments should be
performed according to the standard of care until disease progression,
unacceptable toxicity, or study end. For subjects who have crossed over to
ibrutinib, site visits will be every 9 weeks.
For subjects in the crossover group, questionnaire will be collected until
discontinuation of ibrutinib.
Secondary outcome
Key secondary objectives include evaluations of response rate, overall
survival, 1-year survival rate, duration of response, safety of ibrutinib
compared with temsirolimus, and characterization of the pharmacokinetic profile
of ibrutinib.
PHARMACOKINETIC EVALUATIONS
Model-derived plasma concentrations or metrics of exposure parameters (eg,
minimum observed serum concentration [Cmin] or area under the curve [AUC]) may
be subjected to further analyses to explore pharmacokinetic correlation between
ibrutinib exposure and relevant clinical or biomarker information.
BIOMARKER EVALUATIONS
A tumor sample from lymph node or other organ biopsy collected during
Screening, blood collected at multiple timepoints, and a bone marrow aspirate
will be evaluated to identify markers predictive of response or resistance to
ibrutinib. A lymph node biopsy and bone marrow aspirate should be collected at
progression, if feasible.
SAFETY EVALUATIONS
The safety will be assessed by physical examinations, ECOG criteria for
performance status, laboratory tests, monitoring adverse events, and
concomitant medication usage. Adverse events that occur between the signing of
the informed consent through 30 days following the last dose of ibrutinib or
temsirolimus, or until the start of subsequent anti-MCL therapy will be
collected. The severity of adverse events will be assessed using National
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03.
Intracranial hemorrhage and major hemorrhage have been identified as adverse
events of special interest and will require enhanced reporting and data
collection.
Background summary
Ibrutinib (JNJ 54179060: PCI-32765) is a first-in-class, selective,
irreversible small molecular inhibitor of Bruton*s tyrosine kinase (BTK)
currently being co-developed by Janssen Research & Development, LLC (JRD) and
Pharmacyclics, Inc for the treatment of B-cell malignancies. It has
demonstrated single-agent activity in several B-cell lymphomas, including
relapsed mantle cell lymphoma (MCL), with an acceptable safety profile.A
response rate of approximately 70% was observed in a Phase 2 clinical study of
ibrutinib to treat patients with relapsed/refractory MCL.
Mantle cell lymphoma is a rare and incurable subtype of non-Hodgkin Lymphoma
(NHL).
Intensive therapy is not an option for most patients with MCL because of their
age and comorbidities. Once the disease has progressed after first-line
therapy, the prognosis is dismal. Many agents/regimens have been studied and
are used. However, there is no globally accepted standard treatment for
patients with MCL who progress after initial therapy.
Study objective
The primary hypothesis of this study is that ibrutinib compared with
temsirolimus significantly prolongs PFS in subjects with relapsed or refractory
MCL who have received at least 1 prior rituximab-containing chemotherapy
regimen.
Study design
This is a randomized, controlled, open-label, multicenter, Phase 3 study of
approximately 280 eligible subjects to evaluate the efficacy and safety of
ibrutinib when compared with temsirolimus in subjects with relapsed or
refractory MCL who have received at least 1 prior rituximab-containing
chemotherapy regimen. Subjects will be randomized in a 1:1 ratio and stratified
by the number of prior lines of therapy (1 or 2 vs. * 3); and simplified MCL
international prognostic index (MIPI) (low risk [0-3]; vs. intermediate risk
[4-5]; vs. high risk [6-11]). The efficacy evaluations will be performed by an
IRC that is blinded to study treatment information.
Subjects randomized to Treatment Arm A will receive 560 mg ibrutinib by mouth
once daily on a 21-day cycle. Subjects randomized to Treatment Arm B will
receive intravenous (IV) temsirolimus 175 mg on Days 1, 8, 15 of the first
cycle followed by 75 mg on Days 1, 8, 15 of each 21-day cycle. Treatment on
both arms will continue until disease progression or unacceptable toxicity,
whichever occurs first.
Subjects who received treatment with temsirolimus and have IRC-confirmed
disease progression may be eligible to crossover and receive treatment with
ibrutinib 560 mg orally, daily, on a 21-day cycle until disease progression,
unacceptable toxicity, or study end.
Intervention
see study design
Study burden and risks
Side effects from Ibrutinib and Temsirolimus:
see informed consent and see protocol page 27-29
Side effects of study procedures
Blood Sampling:
The possible side effects of taking blood include pain, bleeding, bruising,
light-headedness, fainting and, on rare occasions, local blood clot formation
or infection with redness and irritation of the vein.
Bone Marrow Sampling:
The possible side effects associated with a bone marrow biopsy include pain,
bleeding, bruising, and infection, as well as a reaction to the numbing agent.
CT scans:
CT scans expose to radiation; Too much radiation over time can lead to the
development of second cancers or leukemia.
Subjects randomized to Treatment Arm A will receive 560 mg ibrutinib by mouth
once daily on a 21-day cycle. Subjects randomized to Treatment Arm B will
receive intravenous (IV) temsirolimus 175 mg on Days 1, 8, 15 of the first
cycle followed by 75 mg on Days 1, 8, 15 of each 21-day cycle. Treatment on
both arms will continue until disease progression or unacceptable toxicity,
whichever occurs first.
Subjects who received treatment with temsirolimus and have IRC-confirmed
disease progression may be eligible to crossover and receive treatment with
ibrutinib 560 mg orally, daily, on a 21-day cycle until disease progression,
unacceptable toxicity, or study end.
The length of time the patient spend in this study will vary and depends on the
response to the treatment. It is anticipated that the study will last
approximately 3 years after the last patient has been randomized into the
study. If the patient stays on the study for the whole duration the patient may
need to visit the study doctor up to 40 times.
If the results of the blood tests are not normal or if the patient is having
side effects, the doctor might reduce the dose of study medication or stop the
treatment altogether.
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Listed location countries
Age
Inclusion criteria
- Confirmed diagnosis of mantle cell lymphoma (MCL);- Received at least 1 prior rituximab-containing chemotherapy regimen (separate lines of therapy are defined as single or combination therapies that are either separated by disease progression or by a > 6 month treatment-free interval);- Documented relapse or disease progression following the last anti-MCL treatment;- At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma;- Eastern Cooperative Oncology Group performance status grade 0 or 1;- Protocol-defined hematology and biochemical laboratory values;Major Inclusion Criteria for Cross Over to Ibrutinib treatment:
- IRC-confirmed disease progression after treatment with temsirolimus, and medical monitor
approval.
- Protocol-defined hematology and biochemical laboratory values
Exclusion criteria
- Prior nitrosoureas within 6 weeks, chemotherapy within 3 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy or other investigational agents within 3 weeks, or major surgery within 4 weeks of randomization;- Prior treatment with temsirolimus, other mTOR inhibitors, ibrutinib, or other Bruton*s tyrosine kinase (BTK) inhibitors;- Known central nervous system lymphoma ;- Received an allogeneic or autologous hematopoietic stem cell transplant <=6 months from the date of randomization and on immunosuppressive therapy or have evidence of active graft versus host disease;- Diagnosed or treated for malignancy other than MCL, except: malignancy treated with curative intent and with no known active disease present for >=3 years before randomization, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated cervical carcinoma in situ without evidence of disease;-Criterion modified per amendment: Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon).
- Criterion modified per amendment: Requires treatment with a strong CYP3A4/5 inhibitor.
- Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification;- Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection or any uncontrolled active systemic infection requiring intravenous antibiotics;- Woman who is pregnant or breast-feeding;- Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator*s opinion, could compromise the subject*s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk;Major Exclusion Criteria for Cross Over to Ibrutinib treatment:
- prior history of stroke or intracranial hemorrhage within 6 months prior to
crossover treatment.
- require anticoagulation with warfarin or equivalent vitamin K antagonists
(eg, phenprocoumon).
- require treatment with a strong CYP3A inhibitor
- clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of pre-crossover screening.
- life-threatening illness, medical condition, or organ system dysfunction which, in the investigator*s opinion, could compromise the subject*s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
- women who are pregnant or breastfeeding
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-000601-74-NL |
| ClinicalTrials.gov | NCT01646021 |
| CCMO | NL41823.029.12 |